Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most important drugs for the treatment of tuberculosis (TB). The pharmacokinetics of all three drugs in the plasma of 24 healthy males were studied as part of a randomized cross-over phase I study of two dosage forms. Subjects ingested single doses of INH at 250 mg, RIF at 600 mg, and PZA at 1,500 mg. Plasma was collected for 36 h and was assayed by high-performance liquid chromatography. The data were analyzed by noncompartmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population modeling methods. Fast and slow acetylators of INH had median peak concentrations in plasma (C[max]) of 2.44 and 3.64 microg/ml, respectively, both of which occurred at 1.0 h postdose (time of maximum concentrations of drugs in plasma [T(max)]), with median elimination half-lives (t1/2) of 1.2 and 3.3 h, respectively (by the NPEM method). RIF produced a median C(max) of 11.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 3.4 h. PZA produced a median C(max) of 28.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 10.0 h. The pharmacokinetic behaviors of INH, RIF, and PZA were well described by the three methods used. These models can serve as benchmarks for comparison with models for other populations, such as patients with TB or TB with AIDS.

Pyrazinamide concentrations and most pharmacokinetic parameters were comparable to those previously published. Apparent half-life was somewhat shorter than that in previous reports. Compared with adults, absorption of pyrazinamide in children appeared more likely to be incomplete or delayed.

Ethambutol (EMB) is the most frequent “fourth drug” used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (± standard deviation) EMB maximum concentration of drug in serum (C max) of 4.5 ± 1.0 μg/ml, time to maximum concentration of drug in serum (T max) of 2.5 ± 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0–∞) of 28.9 ± 4.7 μg · h/ml. In the presence of antacids, subjects had a mean C maxof 3.3 ± 0.5 μg/ml, T max of 2.9 ± 1.2 h, and AUC0–∞ of 27.5 ± 5.9 μg · h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean C max of 3.8 ± 0.8 μg/ml, T max of 3.2 ± 1.3 h, and AUC0–∞ of 29.6 ± 4.7 μg · h/ml. These reductions in C max, delays inT max, and modest reductions in AUC0–∞ can be avoided by giving EMB on an empty stomach whenever possible.

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